Thyroid cancer is the most common type of endocrine neoplasia and the fastest growing cancer type in the U.S. Importantly, only a small proportion of thyroid cancers have aggressive behavior and pose a substantial risk of cancer-related death, whereas the majority of them are indolent and cured by surgical removal. This is particularly true for well-differentiated thyroid papillary and follicular cancers, that have a 5-year survival of >95%, whereas the survival decreases dramatically with tumor dedifferentiation, approaching 50% in poorly differentiated cancer and <10% for anaplastic cancer. In fact, anaplastic thyroid cancer is one of the most lethal types of human cancer with the median patient survival of 5 months after diagnosis. Better understanding of genetic mechanisms of anaplastic thyroid cancer and identification of novel therapeutic targets for these tumors is critical in order to decrease the morbidity and mortality from thyroid cancer. Recently, using the whole-transcriptome (RNA-Seq) analysis followed by additional FISH and RT-PCR analyses, we identified two forms of ALK rearrangements, STRN-ALK and EML4-ALK, in thyroid cancer, including poorly differentiated thyroid cancer and anaplastic thyroid cancer. Moreover, our preliminary data suggest that other types of ALK fusion exist in thyroid tumors and also show that STRN-ALK fusion results in constitutive ALK activity and increase proliferation of thyroid cells. Most importantly, ALK rearrangements that occur in other cancer types are an excellent therapeutic target, and a number of ALK kinase inhibitors have been developed and characterized in pre-clinical and clinical studies, and one of which, crizotinib, has been approved by the FDA for treatment of EML4-ALK-positive lung cancer. If STRN-ALK rearrangement is also tumorigenic and is responsive to inhibition by crizotinib or other ALK inhibitors, it may offe for the first time an effective therapeutic target for already existing drugs in the highly aggressve and most lethal types of thyroid cancer. In the current proposal, we will examine this possibility by testing the hypothesis that ALK rearrangements represent a novel genetic mechanism of aggressive types of thyroid cancer and can serve as a drug target for thyroid cancers. Specifically, we will establish the prevalence of STRN-ALK and other types of ALK rearrangements in thyroid cancer and their role in anaplastic transformation, determine the mechanisms of ALK activation, characterize transforming and tumorigenic properties of ALK rearrangements in thyroid cells, and examine in pre-clinical studies the response of STRN-ALK-positive thyroid cells to ALK inhibitors. The combination of in vitro studies and mouse models should provide us the opportunity to test the growing list of available ALK inhibitors, and hopefully validate for the first time a treatment for the devastating and frequently lethal forms o thyroid cancer.